Radinimmunotherapy of brain tumor

Depite years of intensive research, the prognosis of high-grade gliomas （HGG） remains are highly resistant to currently available therapies. Therefore, there is a need for the development of new therapeutic strategies, such as the use of monoclonal antibodies （MoAbs） in association with radioisotopes, in order to achieve better responses and prognosis. This article deseribes our experience in radionimmunotherapy （RIT） with MoAbs and tumor pre-targeting with the avidin-biotin system.     

Effect of human skin-derived stem cells on vessel architecture, tumor growth, and tumor invasion in brain tumor animal models

Glioblastomas represent an important cause of cancer-related mortality with poor survival. Despite many advances, the mean survival time has not significantly improved in the last decades. New experimental approaches have shown tumor regression after the grafting of neural stem cells and human mesenchymal stem cells into experimental intracranial gliomas of adult rodents. However, the cell source seems to be an important limitation for autologous transplantation in ghoblastoma. In the present study, we evaluated the tumor targeting and antitumor activity of human skin--derived stem cells （hSDSCs） in human brain tumor models. The hSDSCs exhibit tumor targeting characteristics in vivo when injected into the controlateral hemisphere or into the tail vein of mice. When implanted directly into glioblastomas, hSDSCs distributed themselves extensively throughout the tumor mass, reduced tumor vessel density, and decreased anglogenic sprouts.In addition, transplanted hSDSCs differentiate into pericyte cell and release high amounts of human transforming growth factor-betal with low expression of vascular endothehal growth factor, which may contribute to the decreased tumor cell invasion and number of tumor vessels.     

Enhancement of glioblastoma radioresponse by a selective COX-2 inhibitor celecoxib： inhibition of tumor angiogenesis with extensive tumor necrosis

PURPOSE： Toward improved glioblastoma muhiforme treatment, we determined whether celecoxib, a selective cyclooxygenase （COX）-2 inhibitor, could enhance glioblastoma radiosensitivity by inducing tumor necrosis and inhibiting tumor angiogenesis. METHODS AND MATERIALS： U-87MG ceils treated with celecoxib, irradiation, or both were assayed for clonogenic survival and anglogenie factor protein analysis （angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor [VEGF]）. In vivo, survival of mice intracranially implanted with U-87MG ceils and treated with celeeoxib and/or irradiation was monitored. Isolated tumors were assessed for tumor necrosis and tumor microvascular density by yon WiUiebrand＇ s factor （vWF） immunohistochemical staining. RE- SULTS： Celeeoxib （4 and 30 microM; 24, 48, and 72 h） enhanced U-87MG ceil radiosensitivity by significantly reducing clonogenic survival of irradiated cells. Angiopoietin-1 and VEGF proteins were decreased, whereas angiopoietin-2 expression increased after 72 h of celeeoxib alone and when combined with irradiation.     

Attenuation of TGF-β signaling supports tumor progression of a mesenchymal-like mammary tumor cell line in a syngeneic murine model

Previous studies have suggested that TGF-β functions as a tumor promoter in metastatic, mesenchymal-like breast cancer cells and that TGF-β inhibitors can effectively abrogate tumor progression in several of these models. Here we report a novel observation with the use of genetic and pharmacological approaches, and murine mammary cell injection models in both syngeneic and immune compromised mice. We found that TGF-β receptor II (TβRII) knockdown in the MMTV-PyMT derived Py8119, a mesenchymal-like murine mammary tumor cell line, resulted in increased orthotopic tumor growth potential in a syngeneic background and a similar trend in an immune compromised background. Systemic treatment with a small-molecule TGF-β receptor I kinase inhibitor induced a trend towards increased metastatic colonization of distant organs following intracardiac inoculation of Py8119 cells, with little effect on the colonization of luminal-like Py230 cells, also derived from MMTV-PyMT tumors. Taken together, our data suggest that the attenuation of TGF-β signaling in mesenchymal-like mammary tumors does not necessarily inhibit their malignant potential, and anti-TGF-β therapeutic intervention requires greater precision in identifying molecular markers in tumors with an indication of functional TGF-β signaling.     

Prognostic impact of Thomsen–Friedenreich tumor antigen and disseminated tumor cells in the bone marrow of breast cancer patients

Purpose The Thomsen–Friedenreich antigen (TF, CD176) is a specific oncofetal carbohydrate epitope (Galβ1-3GalNAcα-O-Ser/Thr) expressed on the surface of various carcinomas. It mediates endothelium adhesion and formation of metastases. As it also causes immune response, its prognostic impact is indeterminate. The presence of disseminated tumor cells in the bone marrow of breast cancer patients (DTC-BM) indicates worse prognosis. We examined the expression of TF in primary breast cancer tissue of 265 patients with known BM status at the time of first diagnosis. Methods BM aspiration, cytospin preparation and immunocytochemical staining with the anti-Cytokeratin antibody A45 B/B3 was done following a standardised protocol. TF expression was examined immunohistochemically on Tissue Micro Arrays (TMA) with the anti-TF antibody A78-G/A7. Evaluation was done using the immunoreactive score (IRS). Results Median IRS for TF expression was 2 (0–12). 68 of 265 patients (25.7%) showed DTC-BM with a median of 2/2 × 10⁶ cells (1–1500). There was no correlation between TF expression and DTC-BM. After a median follow up of 60.1 months (7–119), the detection of DTC-BM showed prognostic significance for overall survival (OS, p = 0.034), whereas TF positivity (IRS > 2) indicated prolonged disease-free (p = 0.01), distant disease-free (p = 0.005), and overall survival (p = 0.005). Discussion Patients with TF-positive tumors had a significantly better prognosis. Dissemination routes, TF-mediated metastasis formation, and the immunogeneity of TF might determine the prognostic impact of TF expression in different tumor entities. Further characterisation of primary tumors and DTC-BM could help to improve the biological understanding of metastases and develop targeted therapies.     

Glucocorticoids suppress tumor angiogenesis and growth of prostate cancer

Hormone-refractory prostate cancer ( HRPC) sometimes is responsive to treatment with glucocorticoids, such as prednisolone, hydrocortisone and dexamethasone, but the underlying mechanisms are not well established. In a recent paper (Clin Cancer Res, 2006, 12:3003-3009), Yano et al. Hypothesized and confirmed that the therapeutic effect of glucocorticoids on HRPC is attributed to inhibition of angiogenesis. A prostate cancer cell line DU145 that expresses glucocorticoid receptor was used to study the effect of dexamethasone (Dex) on the expres-     

Regulation of the DLG tumor suppressor by β-catenin

The discs-large (DLG) tumor suppressor plays essential roles in regulating cell polarity and proliferation. It localizes at sites of cell-cell contact where it acts as a scaffold for multiple protein interactions, including with the adenomatous polyposis coli (APC) tumor suppressor, which in turn regulates β-catenin. Furthermore, many tumor types including breast and colon have increased levels of β-catenin activity with correspondingly low levels of DLG expression. Here we provide evidence of a direct functional link between these apparently separate phenomena. We show that overexpressed β-catenin can enhance the turnover of DLG in a proteosome dependent manner. This effect is specific to DLG and is not seen with two other PDZ domain-containing targets of β-catenin, MAGI-1 and Scribble. Furthermore, siRNA-mediated ablation of endogenous β-catenin expression also enhances DLG stability. β-catenin-induced degradation of DLG appears to be a consequence of a direct association between the two proteins and requires β-catenin PDZ binding potential. In contrast, the enhanced turnover of DLG requires the unique N-terminal sequences and its PDZ domains. Finally, we also show that the capacity of DLG to inhibit transformed cell growth in an oncogene cooperation assay is inhibited by β-catenin. Taken together these studies suggest that one mechanism by which deregulated β-catenin can contribute to tumorigenesis is through enhancing DLG degradation.     

Advancement of Krüppel-like factor 4 in tumor

KLF4为锌指蛋白转录因子,含特异性转录激活区和转录抑制区,体内分布广泛,在不同的肿瘤组织中,通过抑制细胞增殖、调节细胞分化、细胞凋亡和靶基因的表达,发挥着抑制或促进肿瘤形成的双重作用.其机制可能与乙酰化修饰有关.     

Gene therapeutics: the future of brain tumor therapy?

Primary glioblastoma multiforme is an aggressive brain tumor that has no cure. Current treatments include gross resection of the tumor, radiation and chemotherapy. Despite valiant efforts, prognosis remains dismal. A promising new technique involves the use of oncolytic viruses that can specifically replicate and lyse in cancers, without spreading to normal tissues. Currently, these are being tested in relevant preclinical models and clinical trials as a therapeutic modality for many types of cancer. Results from recent clinical trials with oncolytic viruses have revealed the safety of this approach, although evidence for efficacy remains elusive. Oncolytic viral strategies are summarized in this review, with a focus on therapies used in brain tumors.     

Response of multicellular tumor spheroids to liposomes containing TNF-α

Summary This publication describes a new model to investigate the influence of tumor necrosis factor- (TNF-) on a three-dimensional glial cell aggregate under defined, standardized, reproducible conditions using the glioma cell line A 172.The cells are initially grown as normal monolayer culture until they reach a cell density of up to 1×10⁶. Subsequently they are grown as spheroids by the liquid overlay technique. Spheroids grown in this way were divided into ten groups of more than 50 cell aggregates. Three groups were coincubated with free TNF- in increasing dosages (100 ng/ml, 200 ng/ml and 1000 ng/ml); three groups were incubated with empty liposomes (0.2 mg/ml, 0.4 mg/ml and 2 mg/ml); three groups received liposomes which had been loaded with TNF-, and one group, which received no treatment, served as control.The diameter of the spheroids ranged from 80 m to 350 m. There was no significant difference in growth between the 3 groups treated with free TNF-. Comparing spheroids treated with TNF- with those which had been coincubated with empty liposomes, there was a significant difference (p<0.001) in growth, which correlated with the amount of liposomes. Similarly, free TNF- had a significantly (P<0.001) stronger growth-inhibiting effect as compared to liposomes loaded with TNF-. Comparing the groups treated with liposomes only to those treated with liposomes loaded with TNF-, the latter exhibited a more marked (although not significantly) growth-inhibiting effect.The preliminary conclusion is that the major growth-inhibiting effect seems to be mediated by the liposomes. This phenomenon is in agreement with results obtained in monolayer cultures.     

Advancement of Krüppel-like factor 4 in tumor

KLF4为锌指蛋白转录因子,含特异性转录激活区和转录抑制区,体内分布广泛,在不同的肿瘤组织中,通过抑制细胞增殖、调节细胞分化、细胞凋亡和靶基因的表达,发挥着抑制或促进肿瘤形成的双重作用.其机制可能与乙酰化修饰有关.     

Advancement of Krüppel-like factor 4 in tumor

KLF4为锌指蛋白转录因子,含特异性转录激活区和转录抑制区,体内分布广泛,在不同的肿瘤组织中,通过抑制细胞增殖、调节细胞分化、细胞凋亡和靶基因的表达,发挥着抑制或促进肿瘤形成的双重作用.其机制可能与乙酰化修饰有关.     

Advancement of Krüppel-like factor 4 in tumor

KLF4为锌指蛋白转录因子,含特异性转录激活区和转录抑制区,体内分布广泛,在不同的肿瘤组织中,通过抑制细胞增殖、调节细胞分化、细胞凋亡和靶基因的表达,发挥着抑制或促进肿瘤形成的双重作用.其机制可能与乙酰化修饰有关.     

Inhibitors of Bcl-2 sensitize tumor cells to immune attack

T cells and NKT cells are the major effector lymphocytes in the immune attack against tumor cells.The cytotoxic effect is achieved by inducing apoptosis of tumor target cells.The cytotoxic activity is mediated by perforin/ granzyme-B,Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand(TRAIL).Since killing by these mechanisms is blocked by the anti-apoptotic oncoprotein Bcl-2,which is frequently over-expressed by tumor     

Advancement of Krüppel-like factor 4 in tumor

KLF4为锌指蛋白转录因子,含特异性转录激活区和转录抑制区,体内分布广泛,在不同的肿瘤组织中,通过抑制细胞增殖、调节细胞分化、细胞凋亡和靶基因的表达,发挥着抑制或促进肿瘤形成的双重作用.其机制可能与乙酰化修饰有关.     

Advancement of Krüppel-like factor 4 in tumor

KLF4为锌指蛋白转录因子,含特异性转录激活区和转录抑制区,体内分布广泛,在不同的肿瘤组织中,通过抑制细胞增殖、调节细胞分化、细胞凋亡和靶基因的表达,发挥着抑制或促进肿瘤形成的双重作用.其机制可能与乙酰化修饰有关.